Metabolic disorders comprise a collection of health disorders or risks that increase the risk of morbidity and loss of qualify of life. For example, diabetes, obesity, including central obesity (disproportionate fat tissue in and around the abdomen), atherogenic dyslipidemia (these include a family of blood fat disorders, e.g., high triglycerides, low HDL cholesterol, and high LDL cholesterol that can foster plaque buildups in the vascular system, including artery walls), high blood pressure (130/85 mmHg or higher), insulin resistance or glucose intolerance (the inability to properly use insulin or blood sugar), a chronic prothrombotic state (e.g., characterized by high fibrinogen or plasminogen activator inhibitor-1 levels in the blood), and a chronic proinflammatory state (e.g., characterized by higher than normal levels of high-sensitivity C-reactive protein in the blood), are all metabolic disorders collectively afflicting greater than 50 million people in the United States. In addition, the number of people afflicted with metabolic disorders correlates with increase in age, affecting more than 40 percent of people in their 60s and 70s.
Although treatments for such metabolic disorders do exist, they generally suffer from severe side effects. For example, agonists of the peroxisome proliferator-activated receptor gamma (PPAR gamma) nuclear receptor transcription factor, such as rosiglitazone and pioglitazone, have received regulatory approval for the treatment of type 2 diabetes in the United States and Europe. However, side effects or conditions that can be provoked or aggravated by such thiazolidinedione and non-thiazolidinedione PPAR gamma agonists, including weight gain, fluid retention, peripheral edema, and pulmonary edema, limit the clinical utility and safety of such compounds. Thus, while there are several strategies for treating metabolic disorders, such as obesity predisposition, insulin resistance, high blood pressure, dyslipidemia, etc., the molecular basis for controlling such disorders without provoking or aggravating side effects is unclear, making diagnosis or prognosis of these metabolic disorders problematic and the design of therapeutic agents to treat them quite difficult. Accordingly, there is a great need in the art to identify molecular regulators of metabolic disorders, including the generation of diagnostic, prognostic, and therapeutic agents, such as orally active small molecules, that in turn regulate such molecular regulators so as to effectively control metabolic disorders in subjects.